PROJECT SUMMARY Approximately 115 people are dying every day from an opioid overdose according to CDC/NCHS. Advancements in medication treatment for opioid use disorders (OUD) are greatly needed. Levo-alpha-acetylmethadol (LAAM) offers numerous behavioral and clinical advantages for use in select patients who are not sufficiently managed with methadone and buprenorphine. Despite being approved for OUD treatment, LAAM was withdrawn from market, but not for a lack of safety or effectiveness. We propose to develop novel patentable and more convenient dosage forms of LAAM to offer an additional effective medication to the limited spectrum of products available to treat OUD, and this will provide the necessary incentive for a manufacturer to once again make LAAM available on the market. The formulations proposed are designed for easy manufacture and potentially safer products, and allow selection of the formulation which provides PK levels consistent with the currently approved LAAM oral solution product (ORLAAM). During the UG3 phase, novel LAAM oral dosage forms (i.e., tablets/capsules) and novel buccal film formulations of LAAM will be prepared. Immediate release oral tablet and capsule formulations with various drug loadings will be characterized, including morphology, mechanical property, drug release kinetics in vitro, stability, in order to identify the most promising formulations expected to instantly release LAAM. Using electrospinning to produce LAAM-loaded nanofiber thin film formulations, we will characterize the nanofiber films fully, including morphology, mechanical properties, duration of drug release in vitro, stability of the nanofiber film, mucoadhesive strength ex vivo, the transmucosal diffusion ex vivo, to identify lead formulations expected to steadily release LAAM in animals following buccal administration, and study in vivo for pharmacokinetic profiles as a comparison to LAAM oral solution. At the end of the UG3 phase, we will choose the two lead LAAM formulations with adequate release and stability profiles through optimization studies both in vitro and in vivo. During the UH3 phase, we will carry out a human PK/PD study on the two selected formulations. We will manufacture and fully characterize the lead formulations at the VCU Center for Compounding Practice and Research (CCPR) facility, and then will carry out clinical PK/PD studies and closely monitor the safety (e.g. electrocardiogram) in N=24 nontreatment-seeking subjects with OUD comparing the new formulations at two dose levels to the original approved oral solution through the VCU Center for Clinical and Translational Research (CCTR).